The present invention relates to a method for the preparation of the well-known antidepressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran-carbonitrile.
Citalopram is a well-known antidepressant drug that has now been on the market for some years and has the following structure: 
It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, eg. J. Hyttel Prog. Neuro-Psychopharmacol. and Biol. Psychiat. 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand. 1987, 75, 478-486. The compound has further been disclosed to show effects in the treatment of dementia and cerebrovascular disorders, EP-A 474580.
Citalopram was first disclosed in DE 2,657,013, corresponding to U.S. Pat. No. 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method, which may be used for preparing citalopram.
According to the process described, the corresponding 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile is reacted with 3-(N,N-dimethylamino)propyl-chloride in the presence of methylsulfinylmethide as condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide.
According to the method, which is only outlined in general terms, citalopram may be obtained by ring closure of the compound: 
in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cuprous cyanide. The starting material of Formula II is obtained from 5-bromophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium chloride and N,N-dimethylaminopropyl magnesium chloride, respectively.
A new and surprising method and an intermediate for the preparation of citalopram were described in U.S. Pat. No. 4,650,884, according to which an intermediate of the formula 
is subjected to a ring closure reaction by dehydration with strong sulfuric acid in order to obtain citalopram. The intermediate of Formula III was prepared from 5-cyanophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively.
Further processes are disclosed in International patent applications nos. WO 98/019511, WO 98/019512 and WO 98/019513. WO 98/019512 and WO 98/019513 relate to methods wherein a 5-amino-, 5-carboxy- or 5-(sec. aminocarbonyl)phthalide is subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e. citalopram. International patent application no. WO 98/019511 discloses a process for the manufacture of citalopram wherein a (4-substituted-2-hydroxymethylphenyl-(4-fluorophenyl)methanol compound is subjected to ring closure and the resulting 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran converted to the corresponding 5-cyano derivative which is alkylated with a (3-dimethylamino)propylhalogenide in order to obtain citalopram.
Finally, methods for preparing the individual enantiomers of citalopram are disclosed in U.S. Pat. No. 4,943,590 from which it also appears that the ring closure of the intermediate of Formula III may be carried out via a labile ester with a base.
It has now, surprisingly, been found that citalopram may be manufactured by a novel favourable and safe procedure using convenient starting materials.
Accordingly, the present invention relates to a novel method for the preparation of citalopram comprising reaction of a compound of Formula IV 
with an appropriate oxidising agent such as copper(I) and O2; or NiSO4 and K2S2O8 to afford citalopram 
which is isolated as the base or a pharmaceutically acceptable salt thereof.
In another aspect, the invention relates to methods for preparing the intermediates of Formula IV.
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram as the base or any convenient salt thereof manufactured by the process of the invention.
Furthermore, according to the invention, the compounds of Formula IV may be prepared by different methods.
One of these methods includes the following steps: 
6-carboxy-3-(4-fluorophenyl)phthalide is reacted with an alcohol, R-OH, wherein R is preferably lower alkyl, most preferably Me, in the presence of a dehydrating agent, preferably SOCl2.
The resulting compound of Formula VI is alkylated with 
wherein X is a leaving group in the presence of a suitable base. X is preferably halogen or sulphonate.
Optionally, the alkylating reaction is a stepwise alkylation. In this case, the resulting compound of Formula VI is alkylated with a compound having the formula 
wherein Xxe2x80x2 is a suitable leaving group and Rxe2x80x2 is xe2x80x94CH2xe2x80x94O-Pg, xe2x80x94CH2-NPg1Pg2, xe2x80x94COxe2x80x94N(CH3)2, xe2x80x94CH(OR1)(OR2), xe2x80x94C(OR4)(OR5)(OR6) or xe2x80x94COOR3; wherein Pg is a protection group for an alcohol group, Pg1 and Pg2 are protection groups for an amino group, R1 and R2 are alkyl groups or R1 and R2 together form a chain of 2 to 4 carbon atoms and R3, R4, R5 and R6 are alkyl, alkenyl, alkynyl, aryl or aralkyl;
to form a compound of Formula XVIII 
wherein Rxe2x80x2 is as defined above; followed by conversion of the group Rxe2x80x2 to a dimethylaminomethyl group.
The resulting compound of Formula VII is reacted with a reducing agent such as LiAlH4, Red-Al, AlH3 or activated forms of NaBH4, e.g. NaBH4, Me2SO4; NaBH4, I2; NaBH4, BF3. Et2O; or B2H6; followed by treatment with acid or another dehydrating agent to perform ring closure to form the compound of Formula VIII.
The alcohol of Formula VIII is conveniently activated by tosylchloride or mesylchloride to form the corresponding substituted sulphonate; or the alcohol is converted into the corresponding benzylic halide. This conversion is preferably carried out with SOBr2 or SOCl2.
The corresponding sulphonate or halide is either converted directly to the compound of Formula IV by reaction with liquid ammonia;
or by a reaction with a metal salt of phthalimide, preferably potassium phthalamide followed by treatment with NH2NH2 or by treatment with an amine in an alcohol, i.e. R8NH2/R9xe2x80x94OH, wherein R8 and R9 are lower alkyl, preferably methyl or ethyl, e.g. methylamine in ethanol;
or by a reaction with metal azide, MN3, M preferably being Na or K; followed by treatment with a reducing agent such as Pd/C and H2 or a hydrate source such as LiAlH4 or NaBH4 or an activated form of it.
Another method for preparing the compound of Formula IV includes the following steps: 
6-carboxy-3-(4-fluorophenyl)phthalide is conveniently reacted with a dehydrating agent such as thionylchloride, followed by aminolysis of the resulting activated acid derivative.
The resulting compound of Formula IX is alkylated with 
wherein X is a leaving group in the presence of a suitable base. X is preferably halogen or sulphonate.
Optionally, the alkylating reaction is a stepwise alkylation analogous to the stepwise alkylation described above.
The resulting compound of Formula X is reacted with a reducing agent such as LiAlH4, Red-Al, AlH3 or activated forms of NaBH4, e.g. NaBH4, Me2SO4; NaBH4, I2; NaBH4, BF3.Et2O; or B2H6; followed by treatment with acid or another dehydrating agent to perform ring closure to form the compound of Formula IV.
According to a third method for preparing the compound of Formula IV, the corresponding 6-cyano substituted derivative of 6-carboxy-3-(4-fluorophenyl)phthalide is prepared. 
The carboxy derivative is either reacted with SOCl2 followed by treatment with ammonia and finally a dehydrating agent such as SOCl2 to prepare the cyano derivative of Formula XI; or reacted with an alcohol Rxe2x80x94OH in the presence of acid followed by treatment with ammonia and finally reacted with SOCl2; or reacted in a one-pot process such as with SO2(NH2)2, SOCl2 and sulfolane, or with tert-butylamine, a dehydrating agent such as POCl3 and a suitable solvent, such as toluene.
The resulting compound of Formula XI is alkylated with 
wherein X is a leaving group in the presence of a suitable base. X is preferably halogen or sulphonate.
Optionally, the alkylating reaction is a stepwise alkylation analogous to the stepwise alkylation described above.
The resulting compound of Formula XII is reacted with a reducing agent such as LiAlH4, Red-Al, AlH3 or activated forms of NaBH4, e.g. NaBH4, Me2SO4; NaBH4, I2; NaBH4, BF3.Et2O; or B2H6; followed by treatment with acid to perform ring closure to form the compound of Formula IV.
Other reaction conditions, solvents, etc. for the reactions described above are conventional conditions for such reactions and may easily be determined by a person skilled in the art.
In another aspect, the present invention provides the novel intermediate of Formula V.
In a further aspect, the invention relates to methods for preparing the intermediate of Formula V.
One stepwise process for preparing the intermediate of Formula V is illustrated below: 
m-xylene and p-fluorobenzoyl chloride, which are commercially available compounds are reacted in the presence of AlCl3 to afford the compound of Formula XIV. This compound is oxidised with permanganate, preferably KMnO4 or NaMnO4, giving the resulting compound of Formula XIII, which is finally reacted conveniently with Zn in acid, preferably acetic acid.
Alternatively, the compound of Formula IV is prepared from the compound of Formula XIII by the following stepwise process: 
The compound of Formula XIII is reacted with a reducing agent such as LiAlH4, Red-Al, AlH3 or activated forms of NaBH4, e.g. NaBH4, Me2SO4; NaBH4, I2; NaBH4, BF3.Et2O; or B2H6; followed by treatment with acid to perform ring closure to form the compound of Formula XV.
The alcohol of Formula XV is conveniently activated by tosylchloride or mesylchloride to form the corresponding substituted sulphonate; or the alcohol is converted into the corresponding benzylic halide. This conversion is preferably carried out with SOBr2 or SOCl2.
The corresponding sulphonate or halide is either converted directly to the compound of Formula XVII by reaction with liquid ammonia;
or by a reaction with a metal salt of phthalimide, preferably potassium phthalamide, followed by treatment with NH2NH2 or by treatment with an amine in an alcohol, i.e. R8NH2/R9xe2x80x94OH, wherein R8 and R9 are lower alkyl, preferably methyl or ethyl, e.g. methylamine in ethanol;
or by a reaction with metal azide MN3, M preferably being Na or K; followed by treatment with a reducing agent such as Pd/C and H2 or a hydride source such as LiAlH4 or NaBH4 or an activated form thereof.
The resulting compound of Formula XVII is alkylated with 
wherein X is a leaving group in the presence of a suitable base. X is preferably halogen or sulphonate.
Optionally, the alkylating reaction is a stepwise alkylation analogous to the stepwise alkylation described above.
Optionally the steps of the alkylation and the conversion to the cyano derivative are in opposite order so the conversion to the cyano derivative is performed before the alkylation.
Throughout the specification and claims, the terms lower alkyl or C1-6 alkyl refer to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.
Similarly, alkenyl and alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl.
The term aryl refers to a mono- or bicyclic carbocyclic aromatic group, such as phenyl and naphthyl, in particular phenyl.
The term aralkyl refers to aryl-alkyl, wherein aryl and alkyl are as defined above.
Halogen means chloro, bromo or iodo.
The compound of general Formula I may be used as the free base or as a pharmaceutically acceptable acid addition salt thereof. As acid addition salts, such salts formed with organic or inorganic acids may be used. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
The acid addition salts of the compounds may be prepared by methods known in the art. The base is reacted with either the calculated amount of acid in a water miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooling, or with an excess of the acid in a water immiscible solvent, such as ethylether, ethylacetate or dichloromethane, with the salt separating spontaneously.
The pharmaceutical compositions of the invention may be administered in any suitable way and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of usual sterile solutions for injection.
The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive, colouring, aroma, preservative etc. may be used provided that they are compatible with the active ingredients.
Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilising the solution and filling it in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.